PROJECT SUMMARY Cancer cell survival traits such as suppressed apoptosis, rapid cell cycling and proliferation and the ability to metastasize from a primary location require extensive metabolic reprogramming of the tumor microenvironment. Intriguing new insights into the novel role of metabolic dysregulation in tumorigenesis and metastasis increasingly draw attention to currently understudied areas of cancer research: the potential for metabolic modulation to influence therapeutic outcomes and the impact of metabolic events at the clinical level to impact quality of life for cancer patients. The University of Kentucky (UK) proposes to establish a unique multidisciplinary Center of Biomedical Research Excellence (COBRE) on Cancer and Metabolism (CCM) as a strategically designed, sustainable framework that cultivates cutting-edge research focused on the role of metabolic mediators of cancer development and progression. The proposed multidisciplinary center leverages highly specialized expertise in redox biology, cancer cell signaling, systems biochemistry and data sciences as well as the presence of advanced metabolomics and sophisticated cancer imaging capabilities to create an integrated cancer-metabolism research framework. Overarching goals are to strengthen UK's cancer research enterprise by providing a thematically focused multidisciplinary infrastructure dedicated to defining the contribution of metabolism in the development and treatment of cancer and to use this novel multidisciplinary platform to develop promising early-stage investigators with enhanced skills in an exciting new area of cancer research. To accomplish these goals, we will (1) develop a critical mass of funded investigators with research programs directly related to the Center's unifying theme, (2) provide strong team-based mentoring combining basic and clinical expertise, (3) recruit new investigators to the Center through pilot project grant support leveraged by institutional funds, (4) create synergy among research projects via critical links to strong research centers at UK, including existing COBREs, and (5) facilitate the translation of basic findings in cancer metabolism into early therapeutic approaches. Proposed new synergies will be developed through four research projects, an Administrative Core, important research cores in metabolism and imaging and strong biostatistics/ bioinformatics support, all of which are critical to the proposed studies and will contribute to the development of institutional resources. The scientific focus of the four research projects is cancer-metabolism interactions spanning basic and translational perspectives. This concentration of multidisciplinary expertise focused on a newly recognized cancer paradigm holds promise for significant new understandings of oncogenesis overall. The CCM's integrative thematic focus and the clinical and translational implications of innovative understandings of the cancer-metabolism axis have strong potential to create a cadre of well-trained scientists who are well equipped to lead future generations of scientists integrating these exciting new avenues of investigation in metabolic dysregulation into multi-faceted studies on cancer development and therapy.